The present invention relates to bicyclic imidazo-3-yl amine derivatives substituted on the 6-membered ring, processes for their preparation, methods of treatment using these compounds, and pharmaceutical compositions containing these compounds.
Individual compounds from the class of imidazo-3-yl amines are known to have interesting pharmacological properties. For example, specific imidazo [1,2-a]pyridines are described as antihypertensive substances (GB-B-135,893), as anthelmintics and antimycotics (J. Med. Chem. 1972, 15, 982-985), and as anti-secretory active substances for treating inflammatory conditions (EP-A-0 068 378). EP-A-0 266 890 and J. Med. Chem. 1987, 30, 2031-2046 also describe the action of individual imidazopyridines against inflammatory conditions, particularly gastric inflammatory conditions. Further pharmacological effects described for individual members of the class of imidazo-3-yl amines include antibacterial properties (Chem. Pharm. Bull. 1992, 40, 1170), antiviral properties (J. Med. Chem. 1998, 41, 5108-5112) as well as their action as bezodiazepine receptor antagonists (J. Heterocyclic Chem. 1998, 35, 1205-1217).
In view of these interesting pharmacological properties, various members of the class of substituted imidazo-3-yl amines have been synthesized in the past. In particular, attempts have been made to increase the number of available substituted imidazo-3-yl amines by combinatorial synthesis processes. For example, C. Blackburn et al. in Tetrahedron Lett. 1998, 39, 5469-5472 describe a three-component solid phase synthesis for preparing imidazo-3-yl amines, while Tetrahedron Lett. 1998, 39, 3635-3638 describes a three-component condensation for the parallel synthesis of imidazo-3-yl amines. The synthesis published by K. Groebke et al. in Synlett. 1998, 661-663 is similar to the last-mentioned reaction. H. Bienayme and K. Bouzid in Angew. Chem. 1998, 110 (16), 2349-2352 also describe a multi-component reaction for the combinatorial synthesis of imidazo-3-yl amines, by means of which imidazo-5-amines have also been prepared.
However, the range of possible substituents on the amino nitrogen atom and in the 2-position of the imidazole ring was limited.
Accordingly, the present invention provides further bicyclic imidazo-3-yl amines in which at least one substituent on the amino group and on the atoms of the 6-membered ring not belonging to the imidazole ring as well as the substituent in the 2-position of the imidazole ring are different from hydrogen. In another embodiment, the present invention provides medicaments and pharmaceutical compositions containing these compounds, and methods of treating patients in need thereof with these compounds.
The present invention provides bicyclic imidazo-3-yl amines of general formula I, wherein
X denotes CR4 or N and Y denotes CR6 or N, with the proviso that X and Y do not simultaneously denote N,
R1 denotes (CH2)nCN where n=4, 5 or 6, optionally substituted phenyl, C4-C8-cycloalkyl, CH2CH2R (R=4-morpholino), 1,1,3,3-tetramethylbutyl or CH2Ra wherein Ra denotes hydrogen, OH, C1-C8-alkyl (branched or unbranched), optionally substituted phenyl, CO(OR′) (where R′=unbranched C1-C4-alkyl or branched C1-C5-alkyl), PO(OR′)2 (where R′=unbranched C1-C5-alkyl or branched C1-C6-alkyl) or Si(RxRyRz) (where Rx, Ry and Rz in each case independently of one another denote C1-C4-alkyl (branched or unbranched), C4-C8-alkyl or phenyl,
R2 denotes hydrogen, CORb, wherein Rb denotes C1-C4-alkyl (branched or unbranched) or C3-C8-cycloalkyl, CH2CH2CO(ORc), wherein Rc denotes C1-C4-alkyl (branched or unbranched), adamantyl, optionally substituted phenyl, optionally substituted 1-naphthyl or 2-naphthyl, or in each case optionally substituted 2-pyridyl, 3-pyridyl, 4-pyridyl, thiazolyl or furoyl, CH2phenyl, CH2CH2Rd, wherein Rd denotes optionally substituted phenyl, or CONHRe, wherein Re denotes C1-C8-alkyl (branched or unbranched), C3-C8-cycloalkyl or optionally substituted phenyl,
R3 denotes C1-C8-alkyl (branched or unbranched), C3-C8-cycloalkyl, optionally substituted phenyl, optionally substituted naphthyl, optionally substituted pyrrole, optionally substituted pyridyl, optionally substituted furan, optionally substituted thiophene, optionally substituted anthracene, optionally substituted phenanthrene or optionally substituted quinoline,
R4, R5, R6 and R7 in each case independently of one another denote hydrogen, C1-C4-alkyl (branched or unbranched), NO2, NH2, OH, CF3, Cl, F, Br, CN, COOR, wherein R denotes hydrogen, C1-C4-alkyl (branched or unbranched), OR″, wherein R″ denotes optionally substituted phenyl, optionally substituted benzyl, or C1-C4-alkyl (branched or unbranched), or
R4 and R5, R5 and R6 or R6 and R7 denote a 4-membered carbon bridge optionally containing at least one double bond in which individual C atoms may be optionally replaced by heteroatoms such as N, O or S, and all the remaining radicals R4, R5, R6 and R7 that do not form the bridge denote hydrogen,
with the proviso that at least one of the radicals R4, R5, R6 or R7 present in the molecule is not hydrogen, and if R1 denotes methyl, ethyl, propyl, n-butyl, iso-butyl, CO(O-methyl) or benzyl, R3 does not denote methyl, and if one of the radicals R4, R5, R6 and R7 denotes O-benzyl or R4 denotes OC1-C4-alkyl (branched or unbranched), then R1 does not denote CH2Ra (wherein Ra denotes hydrogen or C1-C5-alkyl (branched or unbranched), in the form of the bases or pharmaceutically acceptable salts.
Preferred compounds according to the invention are those in which R4 denotes hydrogen,
R1 is selected from the group consisting of (CH2)nCN where n=4, 5 or 6, cyclohexyl, CH2CO(O-methyl), 2,6-dimethylphenyl, 1,1,3,3-tetramethylbutyl and n-butyl, and
R3 is selected from the group consisting of 2-pyridyl, 3-pyridyl, 2-furanyl, 2-pyrroyl, methyl, tert-butyl, 3-hydroxyphenyl, 3,4-dimethoxyphenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2-methoxyphenyl, 2,3-dimethoxyphenyl, 3-bromophenyl, 4-bromo-2-fluorophenyl, 5-bromo-2-fluoro-phenyl, 3-bromo-4-fluorophenyl, 3-chlorophenyl, 3,4-dichlorophenyl, 3-fluorophenyl, 3-methylphenyl, 3-phenoxyphenyl, 3-(4-chlorophenoxy)phenyl, 2-chloro-4-fluorophenyl, 2-chloro-6-fluorophenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2-bromophenyl, 2-fluorophenyl, and 2-(trifluoromethyl)-phenyl.
The radicals R4, R5, R6 and R7 are, according to the invention, preferably selected either from the group consisting of hydrogen, NO2, NH2, OH, CF3, Cl, F, Br, CN, methyl and OR″ where R″=benzyl, wherein at least one of the radicals R4, R5, R6 and R7 must be different from hydrogen, or R6 and R7 together form a bridge —CH═CH—CH═CH— and the radicals R4 and R5, insofar as they are present, denote hydrogen.
Particularly preferred according to the invention are bicyclic imidazo-3-yl amine derivatives substituted on the 6-membered ring selected from the group consisting of    7-chloro-2-furan-2-yl-(6-isocyanohexyl)-imidazo[1,2-a]pyrimidine-3,5-diamine,    (5,7-dimethyl-2-pyridin-2-yl-imidazo[1,2-a]-pyrimidin-3-yl)-(6-isocyanohexyl)amine,    7-chloro-(1,1,3,3-tetramethylbutyl)-2-thiopen-2-yl-imidazo[1,2-a]pyrimidine-3,5-diamine,    [6-bromo-2-(2-methoxyphenyl)-imidazo[1,2-a]pyridin-3-yl]-1,1,3,3-tetramethyl]butyl)-amine,    N-[4-(8-benzyloxy-3-cyclohexylaminoimidazo[1,2-a]pyridin-2-yl)-phenyl]-acetamide,    3-(8-benzyloxy-3-butylaminoimidazo[1,2-a]pyridin-2-yl)-phenol,    [8-benzyloxy-2-(3,5-dimethoxyphenyl)-imidazo[1,2-a]pyridin-3-ylamino]-acetic acid methyl ester,    [8-benzyloxy-2-(3,5-dimethoxyphenyl)-imidazo[1,2-a]pyridin-3-yl]-cyclohexylamine,    cyclohexyl-[6,8-dibromo-2-(2-methoxyphenyl)-5-methyl-imidazo[1,2-a]pyridin-3-yl]-amine,    3-[3-(2,6-dimethylphenylamino)-6-nitroimidazo[1,2-a]pyridin-2-yl]-phenol,    [6-bromo-2-(2-methoxyphenyl)-imidazo[1,2-a]pyridin-3-yl]-(1,1,3,3-tetramethylbutyl)-amine,    [6,8-dibromo-2-(2,3-dimethoxyphenyl)-5-methylimidazo[1,2-a]pyridin-3-yl]-(1,1,3,3-tetramethylbutyl)-amine,    cyclohexyl-(2-phenylimidazo[1,2-a]quinolin-1-yl)-amine,    [6-(2-cyclohexyl]-5-methylimidazo[1,2-a]pyridin-3-ylamino)-hexyl]-methylidyne ammonium,    (2,6-dimethylimidazo[1,2-a]pyridin-3-yl)-(1,1,3,3-tetramethylbutyl)-amine,    cyclohexyl-(2,7-dimethylimidazo[1,2-a]pyridin-3-yl)-amine,    cyclohexyl-(2,5,7-trimethylimidazo[1,2-a]pyridin-3-yl)-amine,    [2-(3,4-dimethoxyphenyl)-6-methylimidazo[1,2-a]pyridin-3-yl]-(6-isocyanohexyl)-amine,    (2,7-dimethylimidazo[1,2-a]pyridin-3-yl)-(1,1,3,3-tetramethylbutyl)-amine,    (2,8-dimethyl-imidazo[1,2-a]pyridin-3-yl)-(1,1,3,3-tetramethylbutyl)-amine,    (1,1,3,3-tetramethylbutyl)-(2,5,7-trimethylimidazo[1,2-a]pyridin-3-yl)-amine,    [2-(3,4-dimethoxyphenyl)-7-methylimidazo[1,2-a]pyridin-3-yl]-(6-isocyanohexyl)-amine,    (6-isocyanohexyl)-[2-(2-methoxyphenyl)-6-methyl-imidazo[1,2-a]pyridin-3-yl]-amine,    cyclohexyl-(2-furan-2-yl-6-trifluoromethylimidazo[1,2-a]pyridin-3-yl)-amine,    (8-benzyloxy-2-cyclohexylimidazo[1,2-a]pyridin-3-yl)-cyclohexylamine,    (8-benzyloxy-2-methylimidazo[1,2-a]pyridin-3-yl)-cyclohexylamine,    (8-benzyloxy-2-methylimidazo[1,2-a]pyridin-3-yl)-(1,1,3,3-tetramethylbutyl)-amine,    (8-benzyloxy-2-cyclohexylimidazo[1,2-a]pyridin-3-ylamino)-acetic acid methyl ester,    (8-benzyloxy-2-methylimidazo[1,2-a]pyridin-3-ylamino)-acetic acid methyl ester,    butyl-(2-cyclohexyl-5-propylimidazo[1,2-a]pyridin-3-yl)-amine    N-cylcohexyl-N-(6,8-dichloro-2-furan-2-yl-imidazo[1,2-a]pyridin-3-yl)-acetamide,    N-cylcohexyl-N-(2-furan-2-yl-6-trifluoromethylimidazo[1,2-a]pyridin-3-yl)-acetamide,    N-(8-benzyloxy-2-cyclohexylimidazo[1,2-a]pyridin-3-yl)-N-cyclohexylacetamide,    (5-methyl-2-phenanthren-9-yl-imidazo[1,2-a]pyridin-3-yl)-(1,1,3,3-tetramethylbutyl)-amine,    (2-anthracen-9-yl-7-methylimidazo[1,2-a]pyrimidin-3-yl)-(1,1,3,3-tetramethylbutyl)-amine, and    cyclohexyl-[7-methyl-2-(1-methyl-1H-pyrrol-2-yl)-imidazo[1,2-a]pyrimidin-3-yl]-amine.
Insofar as the bicyclic imidazo-3-yl amine derivatives according to the invention substituted on the 6-membered ring contain optically active carbon atoms, any enantiomer of these compounds, and mixtures thereof in any ratio, are also the subject of the present invention.
The invention also provides medicaments and pharmaceutical compositions containing as an active substance at least one bicyclic imidazo-3-yl amine of general formula I in which R1 to R7, X and Y have the aforementioned meanings, in the form of the base, or in the form of a pharmaceutically acceptable salt, preferably of hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid and/or aspartic acid or in particular of hydrochloric acid.
Surprisingly, the compounds according to the invention are not only potential active substances for the conditions mentioned in the prior art, but also exhibit an analgesic effect.
The medicaments and pharmaceutical compositions according to the invention particularly preferably contain as active substance at least one bicyclic imidazo-3-yl amine selected from the group consisting of    7-chloro-2-furan-2-yl-(6-isocyanohexyl)-imidazo[1,2-a]pyrimidine-3,5-diamine,    (5,7-dimethyl-2-pyridin-2-yl-imidazo[1,2-a]-pyrimidin-3-yl)-(6-isocyanohexyl)amine,    7-chloro-(1,1,3,3-tetramethylbutyl)-2-thiopen-2-yl-imidazo[1,2-a]pyrimidine-3,5-diamine,    [6-bromo-2-(2-methoxyphenyl)-imidazo[1,2-a]pyridin-3-yl]-1,1,3,3-tetramethyyl]butyl)-amine,    N-[4-(8-benzyloxy-3-cyclohexylaminoimidazo[1,2-a]pyridin-2-yl)-phenyl]-acetamide,    3-(8-benzyloxy-3-butylaminoimidazo[1,2-a]pyridin-2-yl)-phenol,    [8-benzyloxy-2-(3,5-dimethoxyphenyl)-imidazo[1,2-a]pyridin-3-ylamino]-acetic acid methyl ester,    [8-benzyloxy-2-(3,5-dimethoxyphenyl)-imidazo[1,2-a]pyridin-3-yl]-cyclohexylamine,    cyclohexyl-[6,8-dibromo-2-(2-methoxyphenyl)-5-methyl-imidazo[1,2-a]pyridin-3-yl]-amine,    3-[3-(2,6-dimethylphenylamino)-6-nitroimidazo[1,2-a]pyridin-2-yl-]-phenol,    [6-bromo-2-(2-methoxyphenyl)-imidazo[1,2-a]pyridin-3-yl]-(1,1,3,3-tetramethylbutyl)-amine,    [6,8-dibromo-2-(2,3-dimethoxyphenyl)-5-methylimidazo[1,2-a]pyridin-3-yl]-(1,1,3,3-tetramethylbutyl)-amine,    cyclohexyl-(2-phenylimidazo[1,2-a]quinolin-1-yl)-amine,    [6-(2-cyclohexyl]-5-methylimidazo[1,2-a]pyridin-3-ylamino)-hexyl]-methylidyne ammonium,    (2,6-dimethylimidazo[1,2-a]pyridin-3-yl)-(1,1,3,3-tetramethylbutyl)-amine,    cyclohexyl-(2,7-dimethylimidazo[1,2-a]pyridin-3-yl)-amine,    cyclohexyl-(2,5,7-trimethylimidazo[1,2-a]pyridin-3-yl)-amine,    [2-(3,4-dimethoxyphenyl)-6-methylimidazo[1,2-a]pyridin-3-yl]-(6-isocyanohexyl)-amine,    (2,7-dimethylimidazo[1,2-a]pyridin-3-yl)-(1,1,3,3-tetramethylbutyl)-amine,    (2,8-dimethyl-imidazo[1,2-a]pyridin-3-yl)-(1,1,3,3-tetramethylbutyl)-amine,    (1,1,3,3-tetramethylbutyl)-(2,5,7-trimethylimidazo[1,2-a]pyridin-3-yl)-amine,    [2-(3,4-dimethoxyphenyl)-7-methylimidazo[1,2-a]pyridin-3-yl]-(6-isocyanohexyl)-amine,    (6-isocyanohexyl)-[2-(2-methoxyphenyl)-6-methyl-imidazo[1,2-a]pyridin-3-yl]-amine,    cyclohexyl-(2-furan-2-yl-6-trifluoromethylimidazo[1,2-a]pyridin-3-yl)-amine,    (8-benzyloxy-2-cyclohexylimidazo[1,2-a]pyridin-2-yl)-cyclohexyl-amine,    (8-benzyloxy-2-methyl-imidazo[1,2-a]pyridin-2-yl)-cyclohexyl-amine,    (8-benzyloxy-2-methylimidazo[1,2-a]pyridin-3-yl)-(1,1,3,3-tetramethylbutyl)-amine,    (8-benzyloxy-2-cyclohexylimidazo[1,2-a]pyridin-3-ylamino)-acetic acid methyl ester,    (8-benzyloxy-2-methylimidazo[1,2-a]pyridin-3-ylamino)-acetic acid methyl ester,    butyl-(2-cyclohexyl-5-propylimidazo[1,2-a]pyridin-3-yl)-amine,    N-cylcohexyl-N-(6,8-dichloro-2-furan-2-yl-imidazo[1,2-a]pyridin-3-yl)-acetamide,    N-cylcohexyl-N-(2-furan-2-yl-6-trifluoromethylimidazo[1,2-a]pyridin-3-yl)-acetamide,    N-(8-benzyloxy-2-cyclohexylimidazo[1,2-a]pyridin-3-yl)-N-cyclohexyl-acetamide,    (5-methyl-2-phenanthren-9-yl-imidazo[1,2-a]pyridin-3-yl)-(1,1,3,3-tetramethylbutyl)-amine,    (2-anthracen-9-yl-7-methylimidazo[1,2-a]pyrimidin-3-yl)-(1,1,3,3-tetramethylbutyl)-amine,    cyclohexyl-[7-methyl-2-(1-methyl-1H-pyrrol-2-yl)-imidazo[1,2-a]pyrimidin-3-yl]-amine, and the pharmaceutically acceptable salts of these compounds.
The compounds according to the invention prove to be effective as ligands for the pain-relevant α2-subtype of the human α-adrenergic receptor. It is therefore particularly preferred to use the bicyclic imidazo-5-yl amine derivatives according to the invention in conjunction with one or more auxiliary substances in order to produce a medicinal drug to control pain.
In order to produce corresponding medicaments or pharmaceutical compositions, in addition to at least one active substance according to the invention auxiliary substances such as carrier materials, fillers, solvents, diluents, colouring agents and/or binders are also used. The choice of auxiliary substances as well as the amounts thereof to be used depends on whether the medicinal drug is to be administered orally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally or topically.
Preparations in the form of tablets, coated tablets, capsules, granules, drops, juices and syrups are suitable for oral application, while solutions, suspensions, readily reconstitutable dry preparations as well as sprays are suitable for parenteral, topical and inhalative administration. Active substances according to the invention in depot form, in dissolved form or in a plaster, optionally with the addition of skin penetration promoting agents, are suitable percutaneous application preparations. Forms of preparation that may be employed orally or percutaneously can provide for the delayed release of the active substances according to the invention.
The amount of active substances to be administered to the patient varies depending on the patient's weight, type of application, medical indication, and the severity of the condition.
The compounds according to the invention are synthesized by reacting amidines of general formula II, in particular 2-aminopyridine- and 2-aminopyrimidine derivatives (commercially available from companies such as Acros, Avocado, Aldrich, Fluka, Lancaster, Maybridge, Merck, Sigma or TCI-Jp), with a variety of ketones, or preferably aldehydes III and isonitriles IV, in the presence of 20% perchloric acid according to a three-component reaction. R1 to R7, X and Y have the meanings specified above for the compounds of formula I. 
In order for the reaction to proceed in a trouble-free manner, the starting compounds are added one after the other in the sequence amidine II, ketone or aldehyde III, and isonitrile IV. The reactions are preferably carried out in dichloromethane at a temperature of preferably 0° C. to 40° C., in particular at a temperature of 10° C. to 20° C.
In order to prepare the compounds according to the invention in which R2* does not denote hydrogen, the compounds Ia formed in the previously described reaction, which preferably have first of all been dissolved in THF, are reacted, depending on the desired end product, with a compound R2Hal wherein Hal denotes bromine, iodine, or particularly chlorine, for example an optionally substituted alkyl, aryl, or acid chloride, or an optionally substituted isocyanate ReNCO in the presence of a morpholine resin (e.g., polystyrene-morpholine from Argonaut) in dichloromethane within 0.25 to 24 hours at temperatures between 10° C. and 40° C. according to the following reaction scheme: 
The excess reagents are then removed from the reaction mixture by filtration through a layer with polymer-bound tris(2-aminoethyl)amine (manufacturer: Novabiochem) or 3-(3-mercaptophenyl)propanamidomethylpolystyrene, and the filtrate is then concentrated, preferably in a vacuum centrifuge. The whole process can be carried out without further intervention in an automated synthesis unit.
The compounds of the formula I can be converted in a known manner into their salts with physiologically compatible acids, preferably with hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid and/or aspartic acid.
Hydrochloric acid is particularly preferred. The salt formation is preferably carried out in a solvent, in particular diethyl ether, diisopropyl ether, alkyl esters of acetic acid, acetone or 2-butanone, or a mixture of these solvents. In order to produce the hydrochlorides, trimethyl silane in aqueous solution may also be used.